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The optimal duration of hormone therapy for locally advanced prostate cancer remains controversial. Since the EORTC 22863 trial, 3 years of adjuvant androgen ablation (AA) with external beam radiation (EBRT) has become the standard of care.

However, previous studies have suggested that AA can have serious side effects, including increased risk of heart disease and diabetes (Keating JCO 2006). Hence, limiting AA to a minimal duration that is effective would allow maximal benefit while minimizing potentially fatal side effects. Furthermore, six months of AA combined with EBRT has been shown to be sufficient to significantly improve five year overall survival compared with EBRT alone (D'Amico JAMA 2004).

The present study compared six months of concomitant and adjuvant AA with EBRT with three years of concomitant and adjuvant AA with EBRT.

Materials and Methods

The present study is a phase III randomized trial. It compared patients treated with EBRT followed by a total of six months of concurrent and adjuvant AA (SADT arm) with patients treated with EBRT and a total of three years of AA (LADT arm).

This study was a non-inferiority study.

Eligible patients:

Patients with T1c-T2b disease with clinical or pathological N1 or N2 disease were eligible for the study. Patients with T2c-T4 disease with N0 to N2 disease were also eligible.

Patients' prostate specific antigen (PSA) level had to be less than 150 ng/ml.

Patients were treated with concurrent EBRT and AA, followed by adjuvant AA, for a total of six months of AA. They were then randomized to no further treatment (SADT) or two and half additional years of AA (LADT arm).

Radiation was given to a dose of 70 Gray to the prostate in 35, 2 Gray fractions over seven weeks. The majority of patients had prostate volume defined using CT imaging (approximately 94%) and dose was prescribed to the planning tumor volume (PTV). Generally three or four field plans were used. Luteinizing hormone releasing agonist monotherapy was used for AA. AA used included triptoreline, goserelin, flutamide, and bicludamide.

Non-inferiority was defined as a mortality hazard ratio (HR) of 1.35 for SADT as compared to LADT. A total of 275 events would be required to demonstrate non-inferiority with 80% power with a one sided p-value of 0.05. A stopping boundary was applied at a one sided p-value of 0.018.

Results

A total of 1117 patients were accrued and of these 970 were randomized between the two arms. Reasons for the exclusion of the 147 patients included toxicity related to treatment, development of a second primary, and patient's refusal to continue with treatment. 483 patients were randomized to the SADT arm and 487 to the LADT arm.

62 patients (12.7%) discontinued treatment on the LADT arm due to toxicity or patient refusal to continue therapy. Ultimately, 19.7% of patients did not complete LADT (this includes patients who discontinued treatment due to disease progression, unknown or other reasons). 63.7% of patients completed three years of treatment and 16.6% were still on AA at the time of analysis.

Global Health Status was used to evaluate the quality of life in the two patient groups and this was found to be similar (p=0.8229).

Patient characteristics between the two groups were well balanced. The median patient age was 69 years. WHO performance status (PS) 0 patients made up 83.4% of the total number of patients. The majority of patients had T3-T4 N0 disease (74.8%).

Median follow up was seven years. Progression (predominantly biochemical or due to osseus metastasis) occurred in 159 patients in the SADT arm and 61 in the LADT arm. These patients were treated with secondary hormone manipulation. Clinical PFS at five years was 81.8% in the LADT arm and 69% in the SADT arm (p<0.0001). Biochemical PFS at five years was 78.27% in the LADT arm and 58.93% in the SADT arm (p<0.0001). PFS results demonstrated the superiority of LADT compared with SADT with hazard ratios of 1.93 and 2.29 for clinical and biochemical PFS, respectively. Five year OS was 85.3% in the LADT arm and 80.6% SADT (HR=1.43, 96.4% confidence interval: 1.04-1.98) and failed to prove non-inferiority.

At a median follow up of 5.2 years 173 patients had died, 100 in the SADT arm and 73 in the LADT arm. Ad hoc interim analysis in September of 2006 demonstrated futility as LADT appeared superior to SADT with a p of 0.0018 and results were disclosed.

Author's Conclusions

The results of this study could not confirm the non-inferiority of the SADT arm of the study. This is the first study to demonstrate that short term AA is not equivalent to three year AA.

PFS was significantly worse in the SADT arm compared with the LADT arm.

At present, long term AA should remain the standard of care for locally advanced prostate cancer.

Clinical/Scientific Implications

The present study is the first to demonstrate that six months on AA in conjunction with EBRT can not be considered non-inferior to three years of AA.

The present study contained node positive patients, though the exact number was not specified, it appeared to be approximately 10%. These patients would normally be treated with long term AA. If these patients were removed from the present study data, it might change the findings of this study. Regardless of the results, removing these patients would provide valuable information regarding the use of six month of AA versus three years of AA in patients with node negative disease.

Combining data from this study as well as previous studies of long term AA (Bolla Lancet 2002), it appears that at present the standard of care for locally advanced prostate cancer is three years of AA with EBRT. These results greatly impact patient care. Previous studies have demonstrated that even with short term use of AA, there is an increased risk of developing heart disease or diabetes (Keating JCO 2006). Furthermore, with the use of AA, there is the risk of loss of bone density and increased risk of pathological fractures. With longer treatment these side effects may be exacerbated.

Prior studies have suggested that intermittent AA may be as effective as continuous AA in the treatment of metastatic disease. Future studies to determine whether intermittent adjuvant AA used in the adjuvant setting is as effective as continuous AA would provide valuable information. Intermittent AA has the potential to limit some of the previously mentioned toxicities.

Jan 6, 2015 - Androgen-deprivation therapy with radiotherapy is associated with a survival advantage over androgen-deprivation therapy alone for older men with locally advanced or screen-detected high-risk prostate cancer, according to a study published online Jan. 5 in the Journal of Clinical Oncology.